The goal of this K08 mentored award is to provide funding for developing the principal investigator (PI) into an independent physician-scientist in the field of cardiovascular disease. The PI, Dr. Amir Rezvan, obtained his MD degree from Iran University of Medical Sciences, followed by an MS degree in Biomedical Science from Drexel University in Philadelphia, where he studied the effects of shear stress on the endothelium. He then completed his Internal Medicine residency at Drexel University and moved to Atlanta to continue his training in Cardiovascular Disease in a four year basic science research track fellowship program at Emory University. He then joined the Division of Cardiology at Emory University as an Assistant Professor. He is currently a licensed physician in the State of Georgia and is certified by the American Board of Internal Medicine in both Internal Medicine and Cardiovascular Disease. He will be allocating 75% of his time to research proposed in this application and 25% of his time to practicing clinical cardiology and teaching residents and fellows in the university setting. This project will focus on the role of shear stress regulated ZBTB46 expression in endothelial cells (ECs) on EC activation. The PI will test the hypothesis that ZBTB46, a transcription repressor responsible for preventing immune activation in dendritic cells, is expressed under laminar shear conditions in ECs and is downregulated by disturbed flow, leading to activation of ECs. The PI will then test the role of shear sensitive miRs with potential targeting of ZBTB46 on its down-regulation by disturbed flow. He will then test the hypothesis that alterations in ZBTB46 levels in ECs (by down-regulating or overexpressing) will alter EC gene expression, specifically potential target genes for ZBTB46 such as NR4A1(NFkB inhibitor), PDGFC, and NFkB mediated genes such as VCAM1 and ICAM1 as well as affecting EC proliferation and tubule formation. Lastly, the PI will test the hypothesis that knockdown of ZBTB46 in an animal model leads to increased endothelial dysfunction and atherosclerosis. Dr. Rezvan will benefit from a team of mentors including Dr. Hanjoong Jo, an established investigator and expert in vascular biology, Dr. W. Robert Taylor, a physician-scientist and expert in vascular inflammation, Dr. Arash Grakoui, an established investigator in the field of immunology, and Dr. Jeremy Boss, an established investigator and expert in gene expression and epigenetics. This group of mentors will provide additional expertise and training needed for the PI to reach his short term goal of achieving scientific independence while furthering the understanding of role of ZBTB46 in EC activation, leading to his long term goal of becoming an established physician-scientist and succeeding in developing novel therapies to prevent and treat atherosclerotic disease while mentoring younger physicians and scientists.